Elevated levels of aldosterone are associated with impaired endothelium-dependent vasodilation in patients with hypertension and congestive heart failure. Although poorly understood, several mechanisms have been implicated to explain the adverse effects of aldosterone on endothelial cell (EEC) function including decreased nitric oxide (NO.) production and/or increased oxidant stress (OS). The applicant has previously demonstrated that glucose-6- phosphate dehydrogenase (G6PD), the first enzyme in the pentose phosphate pathway and principal intracellular source of NADPH, modulates EC function by regulating nitric oxide (NO.) production and limiting vascular OS. Aldosterone-mediated inhibition of G6PD represents a unifying mechanism by which aldosterone may impair EC function and vasodilation. Aldosterone is known to influence gene transcription and inhibition of G6PD, in turn, will result in decreased NO. levels and increased vascular OS to promote EC dysfunction. With the Independent Scientist Award (K02), the applicant will use the time protected by this award examine the molecular mechanisms by which aldosterone modulates G6PD to impair EC function. The applicant will place an intensive research focus on studies that will examine the effect of aldosterone on G6PD expression and the resulting functional consequences in EC in vitro. The in vivo significance of these findings will be confirmed using novel vascular gene transfer techniques and transgenic murine models. The applicant is a principal investigator in the Whitaker Cardiovascular Institute at Boston University School of Medicine, which provides a rich intellectual environment to establish the groundwork for this line of investigation. As evidenced by seven years of vascular biology research, the applicant remains firmly committed to a long-term career in basic science investigation.